Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production

Insulin is an important inhibitor of both hepatic glucose output and hepatic VLDL-triglyceride (VLDL-TG) production. We investigated whether both processes are equally sensitive to insulin-mediated inhibition. To test this, we used euglycemic clamp studies with four increasing plasma concentrations of insulin in wild-type C57Bl/6 mice. By extrapolation, we estimated that half-maximal inhibition of hepatic glucose output and hepatic VLDL-TG production by insulin were obtained at plasma insulin levels of ∼3.6 and ∼6.8 ng/ml, respectively. In the same experiments, we measured that half-maximal decrease of plasma free fatty acid levels and half-maximal stimulation of peripheral glucose uptake were reached at plasma insulin levels of ∼3.0 and ∼6.0 ng/ml, respectively. We conclude that, compared with insulin sensitivity of hepatic glucose output, peripheral glucose uptake and hepatic VLDL-TG production are less sensitive to insulin.

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Insulin as a mediator of hepatic glucose uptake in the conscious dog

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1982.242.2.e97 ◽

1982 ◽

Vol 242 (2) ◽

pp. E97-E101 ◽

Cited By ~ 6

Author(s):

A. D. Cherrington ◽

P. E. Williams ◽

N. Abou-Mourad ◽

W. W. Lacy ◽

K. E. Steiner ◽

...

Keyword(s):

Glucose Uptake ◽

Plasma Insulin ◽

Marked Effect ◽

Glucose Infusion ◽

Hepatic Glucose Output ◽

Intravenous Glucose ◽

Conscious Dog ◽

Hepatic Glucose ◽

Glucose Output ◽

Hepatic Glucose Uptake

The aim of this study was to determine whether a physiological increment in plasma insulin could promote substantial hepatic glucose uptake in response to hyperglycemia brought about by intravenous glucose infusion in the conscious dog. To accomplish this, the plasma glucose level was doubled by glucose infusion into 36-h fasted dogs maintained on somatostatin, basal glucagon, and basal or elevated intraportal insulin infusions. In the group with basal glucagon levels and modest hyperinsulinemia (33 +/- 2 micro U/ml), the acute induction of hyperglycemia (mean increment of 120 mg/dl) caused marked net hepatic glucose uptake (3.7 +/- 0.5 mg . kg-1 . min-1). In contrast, similar hyperglycemia brought about in the presence of basal glucagon and basal insulin levels described net hepatic glucose output in 56%, but did not cause net hepatic glucose uptake. The length of fast was not crucial to the response because similar signals (insulin, 38 +/- 6 micro U/ml; glucose increment, 127 mg/dl) promoted identical net hepatic glucose uptake (3.8 +/- 0.6 mg . kg-1 . min-1) in dogs fasted for only 16 h. In conclusion, in the conscious dog, a) physiologic increments in plasma insulin have a marked effect on the ability of hyperglycemia to stimulate net hepatic glucose uptake, and b) it is not necessary to administer glucose orally to promote substantial net hepatic glucose uptake.

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Severe recurrent hypoglycaemia in a patient with aggressive melanoma

BMJ Case Reports ◽

10.1136/bcr-2021-243468 ◽

2021 ◽

Vol 14 (8) ◽

pp. e243468

Author(s):

Firas Warda ◽

Angela Richter ◽

Kent Wehmeier ◽

Leena Shahla

Keyword(s):

Neck Mass ◽

Hepatic Glucose Output ◽

C Peptide ◽

Insulin Levels ◽

Multiple Organs ◽

Hepatic Glucose ◽

Igf I ◽

Glucose Output ◽

Intravenous Dextrose ◽

Recurrent Hypoglycaemia

. We present a case of hypoglycemia in a young patient without diabetes mellitus who presented initially with enlarging neck mass and weight loss, and was found to have aggressive melanoma with metastasis to multiple organs and diffuse lymphadenopathy. He had presented to the emergency room two times with neuroglycopenic symptoms that required admission and intravenous dextrose continuously. Evaluation of hypoglycemia included C-peptide, insulin levels, insulin-like growth factor (IGF) -I and -II, and ß- hydroxybutyrate. Insulin levels were suppressed appropriately during hypoglycemia, however, IGF-II:IGF-I ratio was high, suggesting non-islet tumour induced hypoglycemia. The presence of IGF-II produced by large tumors results in a low hepatic glucose output and increased uptake by skeletal muscle, resulting in hypoglycemia especially in a patient with extremely low appetite such as our patient. Treating the culprit malignancy leads to resolution of hypoglycemia, but corticosteroids have been used to suppress IGF-II levels and alleviate symptoms.

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Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00396.2014 ◽

2015 ◽

Vol 308 (4) ◽

pp. E306-E314 ◽

Cited By ~ 13

Author(s):

Satya S. Houin ◽

Paul J. Rozance ◽

Laura D. Brown ◽

William W. Hay ◽

Randall B. Wilkening ◽

...

Keyword(s):

Fetal Liver ◽

Hepatic Glucose Production ◽

Plasma Concentrations ◽

Glucose Production ◽

Late Gestation ◽

Fetal Sheep ◽

Fetal Plasma ◽

Hepatic Glucose ◽

Molar Percent ◽

Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

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Hepatic lactate uptake versus leg lactate output during exercise in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00027.2007 ◽

2007 ◽

Vol 103 (4) ◽

pp. 1227-1233 ◽

Cited By ~ 23

Author(s):

H. B. Nielsen ◽

M. A. Febbraio ◽

P. Ott ◽

P. Krustrup ◽

N. H. Secher

Keyword(s):

Blood Flow ◽

Glucose Uptake ◽

Prolonged Exercise ◽

Incremental Exercise ◽

Hepatic Glucose Output ◽

Arterial Lactate ◽

Hepatic Glucose ◽

Lactate Output ◽

Lactate Uptake ◽

Glucose Output

The exponential rise in blood lactate with exercise intensity may be influenced by hepatic lactate uptake. We compared muscle-derived lactate to the hepatic elimination during 2 h prolonged cycling (62 ± 4% of maximal O2 uptake, V̇o2max) followed by incremental exercise in seven healthy men. Hepatic blood flow was assessed by indocyanine green dye elimination and leg blood flow by thermodilution. During prolonged exercise, the hepatic glucose output was lower than the leg glucose uptake (3.8 ± 0.5 vs. 6.5 ± 0.6 mmol/min; mean ± SE) and at an arterial lactate of 2.0 ± 0.2 mM, the leg lactate output of 3.0 ± 1.8 mmol/min was about fourfold higher than the hepatic lactate uptake (0.7 ± 0.3 mmol/min). During incremental exercise, the hepatic glucose output was about one-third of the leg glucose uptake (2.0 ± 0.4 vs. 6.2 ± 1.3 mmol/min) and the arterial lactate reached 6.0 ± 1.1 mM because the leg lactate output of 8.9 ± 2.7 mmol/min was markedly higher than the lactate taken up by the liver (1.1 ± 0.6 mmol/min). Compared with prolonged exercise, the hepatic lactate uptake increased during incremental exercise, but the relative hepatic lactate uptake decreased to about one-tenth of the lactate released by the legs. This drop in relative hepatic lactate extraction may contribute to the increase in arterial lactate during intense exercise.

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Alterations in basal glucose metabolism during late pregnancy in the conscious dog

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.5.e1166 ◽

2000 ◽

Vol 279 (5) ◽

pp. E1166-E1177 ◽

Cited By ~ 18

Author(s):

Cynthia C. Connolly ◽

Linda C. Holste ◽

Lisa N. Aglione ◽

Doss W. Neal ◽

D. Brooks Lacy ◽

...

Keyword(s):

Glucose Metabolism ◽

Hepatic Glucose Production ◽

Late Pregnancy ◽

Nonesterified Fatty Acid ◽

Acid Uptake ◽

Substrate Uptake ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Glucose Output ◽

In Pregnancy

We assessed basal glucose metabolism in 16 female nonpregnant (NP) and 16 late-pregnant (P) conscious, 18-h-fasted dogs that had catheters inserted into the hepatic and portal veins and femoral artery ∼17 days before the experiment. Pregnancy resulted in lower arterial plasma insulin (11 ± 1 and 4 ± 1 μU/ml in NP and P, respectively, P < 0.05), but plasma glucose (5.9 ± 0.1 and 5.6 ± 0.1 mg/dl in NP and P, respectively) and glucagon (39 ± 3 and 36 ± 2 pg/ml in NP and P, respectively) were not different. Net hepatic glucose output was greater in pregnancy (42.1 ± 3.1 and 56.7 ± 4.0 μmol · 100 g liver−1· min−1in NP and P, respectively, P < 0.05). Total net hepatic gluconeogenic substrate uptake (lactate, alanine, glycerol, and amino acids), a close estimate of the gluconeogenic rate, was not different between the groups (20.6 ± 2.8 and 21.2 ± 1.8 μmol · 100 g liver−1· min−1in NP and P, respectively), indicating that the increment in net hepatic glucose output resulted from an increase in the contribution of glycogenolytically derived glucose. However, total glycogenolysis was not altered in pregnancy. Ketogenesis was enhanced nearly threefold by pregnancy (6.9 ± 1.2 and 18.2 ± 3.4 μmol · 100 g liver−1· min−1in NP and P, respectively), despite equivalent net hepatic nonesterified fatty acid uptake. Thus late pregnancy in the dog is not accompanied by changes in the absolute rates of gluconeogenesis or glycogenolysis. Rather, repartitioning of the glucose released from glycogen is responsible for the increase in hepatic glucose production.

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Autoregulation of hepatic glucose production

Acta Endocrinologica ◽

10.1530/eje.0.1380240 ◽

1998 ◽

pp. 240-248 ◽

Cited By ~ 77

Author(s):

MC Moore ◽

CC Connolly ◽

AD Cherrington

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Hepatic Glycogen ◽

Neural Pathways ◽

Hepatic Glucose Output ◽

Counterregulatory Hormones ◽

Hepatic Glucose ◽

Glucose Output

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

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Pressor doses of angiotensin II increase insulin-mediated glucose uptake in normotensive men

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.265.3.e362 ◽

1993 ◽

Vol 265 (3) ◽

pp. E362-E366 ◽

Cited By ~ 4

Author(s):

R. R. Townsend ◽

D. J. DiPette

Keyword(s):

Angiotensin Ii ◽

Glucose Uptake ◽

Whole Body ◽

Glucose Disposal ◽

Hepatic Glucose Output ◽

Hepatic Glucose ◽

Cast Doubt ◽

Normotensive Subjects ◽

Glucose Output ◽

Biochemical Action

The effect of pressor doses of angiotensin II infused intravenously on insulin-mediated glucose uptake was determined in normotensive men. A 3-h hyperinsulinemic euglycemic clamp was employed in 14 normotensive subjects to determine insulin-mediated glucose uptake with or without an infusion of angiotensin II (approximately 15 ng.kg-1.min-1), which increased blood pressure by 20/15 mmHg (systolic/diastolic). Addition of angiotensin II increased whole body glucose uptake by 15% (9.2 +/- 0.5 vs. 10.8 +/- 0.8 mg.kg-1 x min-1; P = 0.011), and glucose oxidation (determined by indirect calorimetry) by 25% (4.0 +/- 0.3 vs. 4.9 +/- 0.4 mg.kg-1 x min-1; P < 0.05) over insulin alone. There was no significant increase in hepatic glucose output during angiotensin II infusion (2.2 +/- 0.1 vs. 2.4 +/- 0.1 mg.kg-1 x min-1; P = NS). We conclude that angiotensin II in pressor doses increases insulin-mediated glucose disposal and oxidation. The mechanism for this may involve a redirection of blood flow into skeletal muscle during angiotensin II infusion or a direct biochemical action of angiotensin II. Although performed in lean normotensive subjects, these results cast doubt on a significant role for angiotensin II in the insulin resistance associated with essential hypertension.

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Influence of somatostatin on glucagon- and epinephrine-stimulated hepatic glucose output in the dog.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1979.236.2.e113 ◽

1979 ◽

Vol 236 (2) ◽

pp. E113

Author(s):

L Saccà ◽

R Sherwin ◽

P Felig

Keyword(s):

Plasma Glucose ◽

Glucose Production ◽

Conscious Dogs ◽

Insulin Deficiency ◽

Hepatic Glucose Output ◽

Glucose Kinetics ◽

Insulin Levels ◽

Hepatic Glucose ◽

Glucose Output ◽

Insulin Replacement

Glucose kinetics were measured using [3-3H]glucose in conscious dogs during the infusion of: 1) glucagon alone; 2) glucagon plus somatostatin with insulin replacement; 3) epinephrine alone; and 4) epinephrine plus somatostatin with insulin and glucagon replacement. Infusion of glucagon alone resulted in a 10-15 mg/dl rise in plasma glucose and a transient 45% rise in glucose production. When somatostatin and insulin were added, a four- to fivefold greater rise in plasma glucose and glucose production was observed. Glucagon levels were comparable to those achieved with infusion of glucagon alone, whereas peripheral insulin levels increased three- to fourfold above baseline, suggesting adequate replacement of preinfusion portal insulin levels. Infusion of epinephrine alone produced a 40% rise in plasma glucose and a 100% rise in glucose production. When somatostatin, insulin, and glucagon were added to epinephrine, the rise in glucose production was reduced in 65% despite replacement of glucagon levels and presumably mild portal insulin deficiency. These findings suggest that somatostatin: 1) potentiates the stimulatory effect of physiologic hyperglucagonemia on glucose production independent of insulin availability and 2) blunts the stimulatory effect of physiologic increments of epinephrine independent of glucagon availability.

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Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1983.245.3.e294 ◽

1983 ◽

Vol 245 (3) ◽

pp. E294-E302 ◽

Cited By ~ 17

Author(s):

L. Sacca ◽

C. Vigorito ◽

M. Cicala ◽

G. Corso ◽

R. S. Sherwin

Keyword(s):

Plasma Insulin ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Base Line ◽

Epinephrine Infusion ◽

Hepatic Glucose ◽

Normal Humans ◽

Glucose Output ◽

Sustained Increase

To evaluate the contribution of gluconeogenesis to epinephrine-stimulated glucose production, we infused epinephrine (0.06 micrograms X kg-1 X min-1) for 90 min into normal humans during combined hepatic vein catheterization and [U-14C]alanine infusion. Epinephrine infusion produced a rise in blood glucose (50-60%) and plasma insulin (30-40%), whereas glucagon levels increased only at 30 min (19%, P less than 0.05). Net splanchnic glucose output transiently increased by 150% and then returned to base line by 60 min. In contrast, the conversion of labeled alanine and lactate into glucose increased fourfold and remained elevated throughout the epinephrine infusion. Similarly, epinephrine produced a sustained increase in the net splanchnic uptake of cold lactate (four- to fivefold) and alanine (50-80%) although the fractional extraction of both substrates by splanchnic tissues was unchanged. We conclude that a) epinephrine is a potent stimulator of gluconeogenesis in humans, and b) this effect is primarily mediated by mobilization of lactate and alanine from extrasplanchnic tissues. Our data suggest that the initial epinephrine-induced rise in glucose production is largely due to activation of glycogenolysis. Thereafter, the effect of epinephrine on glycogenolysis (but not gluconeogenesis) wanes, and epinephrine-stimulated gluconeogenesis becomes the major factor maintaining hepatic glucose production.

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